Generalized thyroid hormone resistance: Identification of an arginine to cystine mutation in codon 315 of the c-erb A beta thyroid hormone receptor

Kenneth D. Burman, Y. Y. Djuh, D. Nicholson, P. Rhoo, L. Wartofsky, H. G. Fein, S. J. Usala, E. H. Hao, W. E.C. Bradley, J. Berard, R. C. Smallridge

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

The present report studies a large kindred (WR) with generalized thyroid hormone resistance that has varying degrees of neuropsychological dysfunction, hyperactivity, poor attention span, decreased IQ and/or abnormalities in spatial perception. In this kindred, there has been found tight linkage of the syndrome with the c-erb A beta gene. The present study was performed to identify the presence of a possible gene mutation as a cause for this syndrome. DNA from peripheral leukocytes was isolated from 15 unaffected and 8 affected individuals from the kindred. Primers encompassing exons 9 (nucleotides 1171–1429) and 10 (nucleotides 1430–1698) were synthesized and used in PCR reactions to amplify these exons. Direct sequencing revealed a consistent substitution in each affected subject, but in none of the unaffected individuals, of a C. to T change in one allele from nucleotide 1243, resulting in an arg to cys change in codon 315. The mutant and wild-type human beta 1 receptors were prepared and their translated proteins were analyzed for T3 binding. The WR T3 receptor from affected patients had reduced T3 binding affinity, with values approximately 2.5 × 1010 M−1 compared to about 5 × 1010 M−1 in normals. In summary, we have: i) identified a consistent and reproducible mutation of a C. to T change in nucleotide 1243 in each of the affected but in none of the unaffected individuals of a large well characterized kindred with generalized thyroid hormone resistance; and ii) noted that the WR allele causes an approximate 50% decrease in the T3 binding affinity. Further studies analyzing the mechanism by which a single point mutation in one allele results in the biochemical and clinical manifestations of generalized thyroid hormone resistance are warranted.

Original languageEnglish (US)
Pages (from-to)573-579
Number of pages7
JournalJournal of endocrinological investigation
Volume15
Issue number8
DOIs
StatePublished - Sep 1992

Keywords

  • Generalized resistance
  • mutation
  • thyroid hormone receptor

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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    Burman, K. D., Djuh, Y. Y., Nicholson, D., Rhoo, P., Wartofsky, L., Fein, H. G., Usala, S. J., Hao, E. H., Bradley, W. E. C., Berard, J., & Smallridge, R. C. (1992). Generalized thyroid hormone resistance: Identification of an arginine to cystine mutation in codon 315 of the c-erb A beta thyroid hormone receptor. Journal of endocrinological investigation, 15(8), 573-579. https://doi.org/10.1007/BF03344927